ODC inhibitors, particularly, DFMO and its pharmaceutically acceptable salts and hydrates, are known to be topically useful in regulating hair growth in mammals, particularly humans (see U.S. Pat. No. 4,720,489 and P.D.R., 55 Edition, 2001, pages 1031-1033).
PCT WO 98/25603 discloses an isomeric pharmaceutical formulation containing DFMO. Examples 7 and 8 respectively teach preparation of a [−]-DFMO containing lotion and topical solution. Patentees teach that the lotion formulation is useful for the treatment or prevention of skin melanoma. The solution is disclosed to be suitable for topical treatment or prevention of proliferative skin disorders. The treatment of such conditions does not require delivery of drug to the hair follicles. More importantly, there is no appreciation whatsoever of enhancement of delivery of DFMO to the skin, much less to the hair follicle. Although Example 7 employs Poloxamer 235, there is no disclosure whatsoever of any advantage for it other than its known use as a co-emulsifier.
U.S. Pat. No. 5,851,537 discloses the topical application of alpha-DFMO monochloride monohydrate for preventing skin cancer. The drug, carried in a hydrophilic cream base, is applied to actinic keratoses. Hydrophilic cream contains 0.025% methyl paraben, 0.015% propyl paraben, 1% sodium lauryl sulfate, 12% propylene glycol, 25% stearyl alcohol, 25% petrolatum and 37% water. There is no disclosure whatsoever of a follicular delivery enhancing component or the desirability of including it. In point of fact, patentees state that the compositions of their invention contain no absorption enhancer.
U.S. Pat. No. 4,720,489 discloses a process for reducing the rate and altering the character of human hair growth. The process comprises applying to the skin a composition containing an ODC inhibitor. Patentees, however, fail to disclose or even appreciate the desirability of targeting the ODC inhibitor to the hair follicle or the need to use a follicular delivery enhancer for such purpose.
U.S. Pat. No. 5,648,394 discloses a topical composition for inhibiting mammalian hair growth. The composition comprises about 1 to 20 parts by weight of a water-soluble, hair-growth-inhibiting drug dispersed in about 99 to 80 parts by weight of an oil-in-water emulsion based vehicle. In parts by weight, the vehicle is comprised of water 78 to 87; glyceryl stearate 2.8 to 4.8; PEG-100 stearate 2.7 to 4.7; cetearyl alcohol 1.9 to 3.3; ceteareth-20 1.6 to 2.7; mineral oil 1.7 to 2.7; stearyl alcohol 1.0 to 2.0; and dimethicone 0.3 to 1.0. Patentees contend that compositions of the invention are superior in efficacy to a water-ethanol composition containing penetration enhancers. They state that this suggests that the compositions of the invention achieve either enhanced skin penetration of the active or increased residence time of the active at the treated site. Patentees, however, fail to teach or even suggest which composition ingredient, or combination of ingredients, accounts for the enhanced skin penetration or increased residence time. Thus, one skilled in the art would attribute it to the entire composition as opposed to any particular composition component or combination of components.
Patentees prepared the vehicles of Examples I and II (see Col. 2 of U.S. Pat. No. 5,648,394). Test compositions containing 2.5, 5, 10, and 15 percent DFMO were then prepared using the two vehicles. A composition containing 10 percent DFMO in water-ethanol was also prepared. The compositions were then tested for hair growth inhibition using the hamster flank model (see Example, Col. 3 of U.S. Pat. No. 5,648,394). The test results (set forth in the table in Column 3 of U.S. Pat. No. 5,648,394) demonstrate that, in each case, the DFMO composition prepared using the vehicle of Example II had a higher percentage of inhibition than the respective DFMO composition prepared using the vehicle of Example I. Consequently, even if one skilled in the art were to select, for example, ceteareth-20, out of the ten ingredients that make up the vehicle, he or she would be led away from the present invention. Although the vehicle of Example II contained less ceteareth-20 than the vehicle of Example I, patentees test results show that the percentage of inhibition obtained with the use of the vehicle of Example II was higher. Thus, if one skilled in the art wishing to increase the percentage of inhibition is led to ceteareth-20, he or she would be led by the teaching of this patent to reduce the amount of ceteareth-20 contained in the composition. The skilled artisan would not increase the amount of ceteareth-20 or, for that matter, the amount of any other ingredient(s) of the vehicle.
The prior art, typified by U.S. Pat. No. 5,648,394, demonstrates the effectiveness of ODC inhibitors for inhibiting hair growth by measuring changes in flank organ hair mass in adult male hamsters treated with ethanol solutions of the ODC inhibitors. The standard hamster flank organ mass study is described in, for example, U.S. Pat. Nos. 4,720,489, 5,095,007, 5,096,911 and 5,132,293.
Prior art topical DFMO compositions generally show relatively low efficacy in humans. Possibly the presumed levels of DFMO achievable in human follicles through use of prior art topical DFMO compositions are insufficient to cause sustained and effective inhibition of target enzyme ornithine decarboxylase (“ODC”).
Complicating matters is the fact that with hair mass analysis, it is very difficult to differentiate the efficacy of different DFMO formulations. This is in part due to physical effects of lotion-based formulations on hamster hair.
The present inventors hypothesized that hair follicle atrophy could represent a surrogate end point for DFMO efficacy.
Clinical studies that were later carried out confirmed that hair follicle atrophy is indeed a valid marker for DFMO efficacy.
The half-life of ODC in the hair follicle is about thirty minutes. In order to block ODC enzyme when it is present in the hair follicle, the ODC inhibitor must be present in the follicle in sufficient amount and for a prolonged duration.
Thus, an aim of the present invention was to identify excipients that would target a high concentration of an ODC inhibitor, preferably DFMO and its pharmaceutically acceptable salts, hydrates, optical enantiomers and racemic mixtures, more preferably Eflornithine, to the hair follicle and, ideally, keep it there for a prolonged duration.
In order to determine differences in the efficacy of DFMO in lotion-based formulations, as well as the onset of action of DFMO, independent of hair growth, the present inventors had to develop a method of analysis of human hair follicle bulbs.
Another goal of the present invention was to develop a formulation that would enhance the delivery of an ODC inhibitor, particularly DFMO and its pharmaceutically acceptable salts, hydrates, optical enantiomers and racemic mixture, to the pilosebaceous unit target site (consisting of the hair follicle, hair shaft and sebaceous gland) and maintain its concentration over a prolonged period of time. Since ornithine decarboxylase has a fifteen-minute to one-hour half-life it is highly desirable that the ODC inhibitor be present in the hair follicle for as long a time as is possible.